The objective of this proposal is to examine developmentally related factors which may influence fetal plasma and amniotic fluid levels of erythropoietin (Ep), erythropoiesis, and regional blood flow in chronically hypoxemic fetal sheep. These investigations are relevant to an understanding of the pathophysiology of neonatal polycythemia, a condition associated with acute and chronic morbidities, including persistent fetal circulation, hyperviscosity syndrome (including seizures), hypoglycemia, and neurological and developmental sequellae. Neonatal polycythemia (packed cell volume greater than or equal to 65%) occurs in 1-3% of all deliveries, although it is often associated with conditions in which acute or chronic hypoxemia in utero is present. Currently available clinical ante- and intrapartum methods to evaluate fetal oxygenation are limited. Ep levels measured in fetal plasma have the potential for providing clinically relevant information regarding fetal well- being. This proposal has three separate but related specific aims which will increase our interpretive understanding of fetal plasma Ep levels. The first is to evaluate the effect of the in vivo P50 on plasma Ep levels in hypoxemic fetal sheep. Fetal hypoxemia will be induced by the intravenous infusion of sodium nitrite resulting in methemoglobin formation, and simultaneous P50 changes will be induced experimentally by fetal pH changes. The second specific aim is to assess the relationship between fetal plasma and urine Ep levels. These will be assessed in the light of fetal metabolic and renal clearances of Ep. Fetuses will be studied under normoxemic as well as sodium nitrite induced hypoxemic steady state conditions in early (less than 120 d) and late (greater than 130 d) gestation. The third and final specific aim will be to study the fetal effects of 12 days of chronic fetal nitrite induced hypoxemia beginning at 125 plus or minus 3 days' gestation. Changes in erythropoietic (Ep, Hb, reticulocytes, and red cell mass), hemodynamic (blood pressure, heart rate, whole blood viscosity, and regional blood flow), and growth parameters (organ and body weights, and length measurements) will be examined.
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